EDITORIAL
Why Do We Need Another Tumor Regression Grading System for Rectal Cancer After Neoadjuvant Therapy? Rodrigo O. Perez, M.D., Ph.D. São Paulo, Brazil
T
he exposure of primary rectal cancer to radiation with or without chemotherapy may result in significant tumor cell death leading to tumor size reduction (downsizing) and a shift toward earlier disease staging through sterilization of deeper layers of the tumor and metastatic perirectal nodes (downstaging).1 Ultimately, the population of tumor cells within the cancer may be reduced and replaced by fibrosis or scarring of the rectal wall. In this setting, attempts have been made to quantify this reduction in cancer population and replacement by normal tissue. Various grading systems have been proposed, mostly derived from experience with other solid cancers treated by radiation therapy, to provide a relevant and clinically useful prognostic feature. Common between all grading systems is the percentage of tumor cells relative to fibrosis as the primary parameter used for classification. Therefore, on 1 end of the spectrum is the absence (0%) of residual cancer cells (complete pathological response – pCR), whereas the other end represents tumors with little or no tumor cell death, resulting in nearly 100% residual cancer cells. However logical they may seem, these classification systems have suffered from significant limitations to be fully implemented into clinical practice.2 The 2 different ends of the spectrum have obvious contrasting differences in all major oncological outcomes, because patients with pCR are associated with excellent results in terms of local disease control and survival. The problems reside in the intermediate groups between complete and no response to therapy. These intermediate groups have been subdivided in 1, 2, and even 3 subgroups based on subjective patterns of response to therapy.3 Financial Disclosure: None reported. Correspondence: Rodrigo Oliva Perez, M.D., Ph.D., Rua Manoel da Nóbrega 1564, São Paulo – SP, Brazil, 04001-005. E-mail: rodrigo.operez@ gmail.com Dis Colon Rectum 2015; 58: 1–2 DOI: 10.1097/DCR.0000000000000253 © The ASCRS 2014 Diseases of the Colon & Rectum Volume 58: 1 (2015)
The lack of standardization of these grading systems has also contributed to difficulties in their widespread implementation. In addition, the actual grading by pathologists of tumor regression may be quite challenging because of the subjective nature of the histological interpretation of response. This could potentially lead to nonreproducible findings. In fact, a recent study resulted in poor concordance among different experienced pathologists regardless of the tumor regression grading (TRG) system used.4 Finally, many of these grading systems failed to demonstrate independent correlation with oncological outcomes, particularly within intermediate responses, in patients with rectal cancer after chemoradiation (CRT) and surgery, seriously questioning the usefulness of this information in clinical practice.2,3,5–7 So perhaps we do need another TRG system. In the current edition of Diseases of the Colon & Rectum, Kalady and colleagues8 have elegantly reviewed the outcomes of patients with rectal cancer following neoadjuvant CRT with respect to a “new” TRG system. In fact, at a first glance, the grading system proposed by the American Joint Committee on Cancer/College of American Pathologists seems to solve all the issues because it provides clinically relevant prognostic information to these patients and a proposition for the standardization of TRG nationwide. In addition, the authors were able to demonstrate for the first time, for this particular grading system, that it works across the board to all subcategories of response. Therefore, not only pCR is different from no response to CRT, but also, intermediate categories have distinct oncological outcomes statistically different from each other. Finally, oncological outcomes were independent from other prognostic features frequently not tested in many studies for alternative tumor regression grading systems. However promising this American Joint Committee on Cancer/College of American Pathologists TRG system may be, there are a few challenges that need to be addressed. In this first study to demonstrate its clinical relevance, inherent limitations may suggest the next steps required for its widespread implementation. First, this hypothesis needs to be validated in a prospective study, preferably by more than one institution to avoid all potential biases. This is reflected by the variety of different treatment regimens, including 1
2
radiation therapy doses and chemotherapy used during the study, as well as the different pathology practices. We know that these features may influence tumor response to CRT.9 Second, when histological tumor regression is the parameter of choice, the interval between CRT and surgery is of paramount relevance. Ultimately, patients with incomplete response at 6 weeks may become pCR at 12 weeks.10 Therefore, standardization of the interval in this particular setting is crucial. A third relevant issue is the standardization of adjuvant systemic chemotherapy. Both indication for and the exact regimen may be quite relevant in disease-free survival and overall survival of these patients and are currently being investigated through prospective clinical trials. Even though the use of adjuvant chemotherapy was not an independent predictor of oncological outcome in the present study, the absence of clear selection criteria or standardized regimens may have contributed to this finding. Finally, reproducibility is a key issue in any given medical test or procedure. The grading system may only prove to be useful if other pathologists in standard clinical practice reproduce the findings. Even though the use of multiple pathologists for the assessment of TRG used in the study may reflect a “real life” situation of pathologists around the country, proper reproducibility tests are warranted to understand its true validity. Ultimately, pathologists from the same high-volume institution may not result in same grading findings from multiple pathologists in different low-volume centers.4 So, do we need another TRG system? The answer: maybe, if these challenges are to be addressed and this “new” TRG system is proven to be actually clinically relevant. Otherwise, this TRG system will add to the long list of TRGs used with little impact on the management of patients. In fact, the widespread implementation of radiological assessment of TRG has been shown to be associated with final pathology and survival outcomes.11 Ultimately, magnetic resonance TRG may turn out to be more clinically relevant in allowing the tailoring of surgical and even nonsurgical management of these patients after CRT. Finally, the continuous implementation of newer neoadjuvant regimens, including regimens without radiation therapy, may require the issue of TRG to be frequently revisited in the near future. These are important issues to be considered before embarking on this laborious journey.
Editorial
REFERENCES 1. Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results–EORTC 22921. J Clin Oncol. 2005;23:5620–5627. 2. Vallböhmer D, Bollschweiler E, Brabender J, et al. Evaluation of histological regression grading systems in the neoadjuvant therapy of rectal cancer: do they have prognostic impact? Int J Colorectal Dis. 2012;27:1295–1301. 3. Beddy D, Hyland JM, Winter DC, et al. A simplified tumor regression grade correlates with survival in locally advanced rectal carcinoma treated with neoadjuvant chemoradiotherapy. Ann Surg Oncol. 2008;15:3471–3477. 4. Chetty R, Gill P, Govender D, et al. International study group on rectal cancer regression grading: interobserver variability with commonly used regression grading systems. Hum Pathol. 2012;43:1917–1923. 5. Vecchio FM, Valentini V, Minsky BD, et al. The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer. Int J Radiat Oncol Biol Phys. 2005;62:752–760. 6. Bujko K, Kolodziejczyk M, Nasierowska-Guttmejer A, et al; Polish Colorectal Cancer Group. Tumour regression grading in patients with residual rectal cancer after preoperative chemoradiation. Radiother Oncol. 2010;95:298–302. 7. Abdul-Jalil KI, Sheehan KM, Kehoe J, et al. The prognostic value of tumour regression grade following neoadjuvant chemoradiation therapy for rectal cancer. Colorectal Dis. 2014;16:O16–O25. 8. Mace AG, Pai RK, Stocchi L, Kalady MF. American Joint Committee on Cancer and College of American Pathologists Regression Grade: a new prognostic factor in rectal cancer. Dis Colon Rectum. 2015:58:32–44. 9. Sanghera P, Wong DW, McConkey CC, Geh JI, Hartley A. Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response. Clin Oncol (R Coll Radiol). 2008;20:176–183. 10. Kalady MF, de Campos-Lobato LF, Stocchi L, et al. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg. 2009;250:582–589. 11. Patel UB, Taylor F, Blomqvist L, et al. Magnetic resonance imaging-detected tumor response for locally advanced rectal cancer predicts survival outcomes: MERCURY experience. J Clin Oncol. 2011;29:3753–3760.
Why Do We Need Another Tumor Regression Grading System for Rectal Cancer After Neoadjuvant Therapy? Rodrigo O. Perez, M.D., Ph.D. São Paulo, Brazil
T
he exposure of primary rectal cancer to radiation with or without chemotherapy may result in significant tumor cell death leading to tumor size reduction (downsizing) and a shift toward earlier disease staging through sterilization of deeper layers of the tumor and metastatic perirectal nodes (downstaging).1 Ultimately, the population of tumor cells within the cancer may be reduced and replaced by fibrosis or scarring of the rectal wall. In this setting, attempts have been made to quantify this reduction in cancer population and replacement by normal tissue. Various grading systems have been proposed, mostly derived from experience with other solid cancers treated by radiation therapy, to provide a relevant and clinically useful prognostic feature. Common between all grading systems is the percentage of tumor cells relative to fibrosis as the primary parameter used for classification. Therefore, on 1 end of the spectrum is the absence (0%) of residual cancer cells (complete pathological response – pCR), whereas the other end represents tumors with little or no tumor cell death, resulting in nearly 100% residual cancer cells. However logical they may seem, these classification systems have suffered from significant limitations to be fully implemented into clinical practice.2 The 2 different ends of the spectrum have obvious contrasting differences in all major oncological outcomes, because patients with pCR are associated with excellent results in terms of local disease control and survival. The problems reside in the intermediate groups between complete and no response to therapy. These intermediate groups have been subdivided in 1, 2, and even 3 subgroups based on subjective patterns of response to therapy.3 Financial Disclosure: None reported. Correspondence: Rodrigo Oliva Perez, M.D., Ph.D., Rua Manoel da Nóbrega 1564, São Paulo – SP, Brazil, 04001-005. E-mail: rodrigo.operez@ gmail.com Dis Colon Rectum 2015; 58: 1–2 DOI: 10.1097/DCR.0000000000000253 © The ASCRS 2014 Diseases of the Colon & Rectum Volume 58: 1 (2015)
The lack of standardization of these grading systems has also contributed to difficulties in their widespread implementation. In addition, the actual grading by pathologists of tumor regression may be quite challenging because of the subjective nature of the histological interpretation of response. This could potentially lead to nonreproducible findings. In fact, a recent study resulted in poor concordance among different experienced pathologists regardless of the tumor regression grading (TRG) system used.4 Finally, many of these grading systems failed to demonstrate independent correlation with oncological outcomes, particularly within intermediate responses, in patients with rectal cancer after chemoradiation (CRT) and surgery, seriously questioning the usefulness of this information in clinical practice.2,3,5–7 So perhaps we do need another TRG system. In the current edition of Diseases of the Colon & Rectum, Kalady and colleagues8 have elegantly reviewed the outcomes of patients with rectal cancer following neoadjuvant CRT with respect to a “new” TRG system. In fact, at a first glance, the grading system proposed by the American Joint Committee on Cancer/College of American Pathologists seems to solve all the issues because it provides clinically relevant prognostic information to these patients and a proposition for the standardization of TRG nationwide. In addition, the authors were able to demonstrate for the first time, for this particular grading system, that it works across the board to all subcategories of response. Therefore, not only pCR is different from no response to CRT, but also, intermediate categories have distinct oncological outcomes statistically different from each other. Finally, oncological outcomes were independent from other prognostic features frequently not tested in many studies for alternative tumor regression grading systems. However promising this American Joint Committee on Cancer/College of American Pathologists TRG system may be, there are a few challenges that need to be addressed. In this first study to demonstrate its clinical relevance, inherent limitations may suggest the next steps required for its widespread implementation. First, this hypothesis needs to be validated in a prospective study, preferably by more than one institution to avoid all potential biases. This is reflected by the variety of different treatment regimens, including 1
2
radiation therapy doses and chemotherapy used during the study, as well as the different pathology practices. We know that these features may influence tumor response to CRT.9 Second, when histological tumor regression is the parameter of choice, the interval between CRT and surgery is of paramount relevance. Ultimately, patients with incomplete response at 6 weeks may become pCR at 12 weeks.10 Therefore, standardization of the interval in this particular setting is crucial. A third relevant issue is the standardization of adjuvant systemic chemotherapy. Both indication for and the exact regimen may be quite relevant in disease-free survival and overall survival of these patients and are currently being investigated through prospective clinical trials. Even though the use of adjuvant chemotherapy was not an independent predictor of oncological outcome in the present study, the absence of clear selection criteria or standardized regimens may have contributed to this finding. Finally, reproducibility is a key issue in any given medical test or procedure. The grading system may only prove to be useful if other pathologists in standard clinical practice reproduce the findings. Even though the use of multiple pathologists for the assessment of TRG used in the study may reflect a “real life” situation of pathologists around the country, proper reproducibility tests are warranted to understand its true validity. Ultimately, pathologists from the same high-volume institution may not result in same grading findings from multiple pathologists in different low-volume centers.4 So, do we need another TRG system? The answer: maybe, if these challenges are to be addressed and this “new” TRG system is proven to be actually clinically relevant. Otherwise, this TRG system will add to the long list of TRGs used with little impact on the management of patients. In fact, the widespread implementation of radiological assessment of TRG has been shown to be associated with final pathology and survival outcomes.11 Ultimately, magnetic resonance TRG may turn out to be more clinically relevant in allowing the tailoring of surgical and even nonsurgical management of these patients after CRT. Finally, the continuous implementation of newer neoadjuvant regimens, including regimens without radiation therapy, may require the issue of TRG to be frequently revisited in the near future. These are important issues to be considered before embarking on this laborious journey.
Editorial
REFERENCES 1. Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results–EORTC 22921. J Clin Oncol. 2005;23:5620–5627. 2. Vallböhmer D, Bollschweiler E, Brabender J, et al. Evaluation of histological regression grading systems in the neoadjuvant therapy of rectal cancer: do they have prognostic impact? Int J Colorectal Dis. 2012;27:1295–1301. 3. Beddy D, Hyland JM, Winter DC, et al. A simplified tumor regression grade correlates with survival in locally advanced rectal carcinoma treated with neoadjuvant chemoradiotherapy. Ann Surg Oncol. 2008;15:3471–3477. 4. Chetty R, Gill P, Govender D, et al. International study group on rectal cancer regression grading: interobserver variability with commonly used regression grading systems. Hum Pathol. 2012;43:1917–1923. 5. Vecchio FM, Valentini V, Minsky BD, et al. The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer. Int J Radiat Oncol Biol Phys. 2005;62:752–760. 6. Bujko K, Kolodziejczyk M, Nasierowska-Guttmejer A, et al; Polish Colorectal Cancer Group. Tumour regression grading in patients with residual rectal cancer after preoperative chemoradiation. Radiother Oncol. 2010;95:298–302. 7. Abdul-Jalil KI, Sheehan KM, Kehoe J, et al. The prognostic value of tumour regression grade following neoadjuvant chemoradiation therapy for rectal cancer. Colorectal Dis. 2014;16:O16–O25. 8. Mace AG, Pai RK, Stocchi L, Kalady MF. American Joint Committee on Cancer and College of American Pathologists Regression Grade: a new prognostic factor in rectal cancer. Dis Colon Rectum. 2015:58:32–44. 9. Sanghera P, Wong DW, McConkey CC, Geh JI, Hartley A. Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response. Clin Oncol (R Coll Radiol). 2008;20:176–183. 10. Kalady MF, de Campos-Lobato LF, Stocchi L, et al. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg. 2009;250:582–589. 11. Patel UB, Taylor F, Blomqvist L, et al. Magnetic resonance imaging-detected tumor response for locally advanced rectal cancer predicts survival outcomes: MERCURY experience. J Clin Oncol. 2011;29:3753–3760.
